MODULATION OF NORADRENALINE RELEASE FROM THE SYMPATHETIC-NERVES OF THE HUMAN SAPHENOUS-VEIN AND PULMONARY-ARTERY BY PRESYNAPTIC EP(3)-RECEPTOR AND DP-RECEPTOR

1 Spirally cut strips of the human saphenous vein and pulmonary artery were used to determine the pharmacological properties of the presynap tic prostanoid receptors involved in the modulation of sympathetic [H- 3]-noradrenaline release. Strips preincubated with [H-3]-noradenaline were superfused with physiological salt solution containing inhibitors of uptake(1) and uptake(2) and rauwolscine to eliminate involvement o f presynaptic alpha(2)-adrenoceptors. Tritium overflow was evoked by t ransmural electrical stimulation (standard frequency: 2 Hz). 2 In the saphenous vein, prostaglandin E(2) (PGE(2)) inhibited the electrically -evoked tritium overflow; at the highest concentration investigated, t ritium overflow was inhibited by more than 75% and the pEC(50) value w as 7.00. These effects were mimicked by prostaglandin E(1), the EP(1)/ EP(3) receptor agonist, sulprostone and the EP(2)/EP(3) receptor agoni st, misoprostol with the rank order(pEC(50)): sulprostone (8.60)>PGE(1 ) (7.25)> misoprostol (6.96). This rank order of potency suggests that the inhibitory effect of the drugs is mediated by presynaptic EP(3)-r eceptors. In contrast, PGF(2 alpha), did not inhibit evoked tritium ov erflow; the IP/EP(1) receptor agonist iloprost and the stable thrombox ane A(2) analogue U 46619 (9, 11-dideoxy-11 alpha,9 alpha-epoxy-methan oprostaglandin F-2 alpha) produced inhibition only at concentrations a bove 1 mu M. 3 The EP(1)-receptor antagonist, AH 6809 (6-isopropoxy-9- oxoxanthene-2-carboxylic acid) had no effect on the evoked tritium ove rflow nor did it modify the inhibitory effect of PGE(2), further exclu ding involvement of inhibitory presynaptic EP(1)-receptors. 4 PGD(2) c aused a facilitation of evoked tritium overflow in the saphenous vein; this facilitation is probably mediated by presynaptic DP-receptors, s ince it was abolished by the selective DP-receptor antagonist, BW A868 C l)-1-(2-cyclohexyl-2-hydroxyethylamino)hydantoin). 5 In the pulmonar y artery, sulprostone (pEC(50) value 8.35), misoprostol (7.70) and PGE (2) (6.80) inhibited electrically-evoked tritium overflow. This rank o rder of potency is consistent with the involvement of inhibitory presy naptic EP(3)-receptors. 6 These results suggest that the sympathetic n erve fibres of both human saphenous vein and pulmonary artery are endo wed with presynaptic inhibitory EP(3) receptors. The EP(3)-receptors d o not interact with the alpha(2)-autoreceptors. In addition, the human saphenous vein seems to be endowed with presynaptic facilitatory DP-r eceptors.